Method for the production of 1-amino-3-phenyl- uracil derivatives

ABSTRACT

The present invention relates to a novel process for preparing known 1-amino-3-phenyluracil derivatives (1-amino-3-phenyl-2,4(1H,3H)pyrimidinedione derivatives) and novel 1-amino-6-hydroxy-3-phenyldihydro-2,4(1H,3H)pyrimidinedione derivatives of the formula (II)  
                 
 
     in which  
     R 1  is hydrogen, cyano, nitro or halogen,  
     R 2  is cyano, nitro, halogen or optionally substituted alkyl or alkoxy,  
     R 3  is hydrogen, hydroxyl, mercapto, amino, hydroxyamino, hydrazino, halogen, or one of the radicals —R 6 , -Q-R 6 , —NH—R 6 , —NH—O—R 6 , —NH—SO 2 —R 6 , —N(SO 2 —R 6 ) 2 , —CQ 1 -R 6 , —CQ 1 -Q 2 -R 6 , —CQ 1 -NH—R 6 , -Q 2 -CQ 1 -R 6 , —NH—CQ 1 -R 6 , N(SO 2 —R 6 )(CQ 1 -R 6 ), -Q 2 -CQ 1 -Q 2 -R 6 , —NH—CQ 1 -Q 2 -R 6  or -Q 2 -CQ 1 -NH—R 6 ,  
     where  
     Q is O, S, SO or SO 2 ,  
     Q 1  and Q 2  are each independently oxygen or sulphur and  
     R 6  is optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl,  
     R 4  is hydrogen, halogen or optionally substituted alkyl, and  
     R 5  is fluorine- and/or chlorine-substituted alkyl,  
     as intermediates therefor and to a process for preparing them.

[0001] The present invention relates to a novel process for Preparingknown 1-amino-3-phenyluracil derivatives(1-amino-3-phenyl-2,4(1H,3H)pyrimidinedione derivatives) and novel1-amino-6-hydroxy-3-phenyldihydro-2,4(1H,3H)pyrimidinedione derivativesas intermediates therefore and to a process for preparing them.

[0002] It has already become known that certain 3-amino-1-phenyluracilscan be prepared by reacting amino alkenoic esters with substitutedphenylisocyanates or with substituted phenylurethanes in the presence ofbases and reacting the resulting 1-phenyluracils with1-aminooxy-2,4-dinitrobenzene (cf. EP-A-648 749, U.S. Pat. No.5,593,945, U.S. Pat. No. 5,681,794, U.S. Pat. No. 6,110,870,WO-A-95/29168, U.S. Pat. No. 5,759,957, U.S. Pat. No. 5,962,372).However, a disadvantage of this process is that the desired productsoccur in relatively low yields and not always in sufficient quality.Also, the starting materials required have little suitability for thepreparation on the industrial scale.

[0003] It is further already known that certain1,3-oxazine-2,4(3H)diones which are unsubstituted on the nitrogen atomreact with hydrazine to give uracils which bear an amino group assubstituents. In contrast, the corresponding reaction of1,3-oxazine-2,4(3H)diones which are substituted on the nitrogen atomresults not in uracils but only pyrazole derivatives (cf. J. Heterocycl.Chem. 15 (1978), 1475-1478).

[0004] Finally, it is already known that 3-amino-1-phenyluracilderivatives can also be obtained by reacting substitutedphenyloxazinediones with hydrazine hydrate or with acid adducts ofhydrazine (cf. WO-A-98/27068). However, the yield and quality of theproducts obtained in this way are not entirely satisfactory.

[0005] It has now been found that 1-amino-3-phenyluracil derivatives(1-amino-3-phenyl-2,4(1H,3H)pyrimidinedione derivatives) of the generalformula (I)

[0006] in which

[0007] R¹ is hydrogen, cyano, nitro or halogen,

[0008] R² is cyano, nitro, halogen or optionally substituted alkyl oralkoxy,

[0009] R³ is hydrogen, hydroxyl, mercapto, amino, hydroxyamino,hydrazino, halogen, or one of the radicals —R⁶, -Q-R⁶, —NH—R⁶, —NH—O—R⁶,—NH—SO₂—R⁶, —N(SO₂—R⁶)₂—CQ¹-R⁶, —CQ¹-Q²-R⁶, —CQ¹-NH—R⁶, Q²-CQ¹-R⁶,NH-CQ¹-R⁶, —N(SO₂—R⁶)(CQ¹-R⁶)-Q²-CQ¹-Q²-R⁶, —NH—CQ-Q²-R⁶ or-Q²-CQ¹-NH—R⁶,

[0010] where

[0011] Q is O, S, SO or SO₂,

[0012] Q¹ and Q² are each independently oxygen or sulphur and

[0013] R⁶ is optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl,

[0014] R⁴ is hydrogen, halogen or optionally substituted alkyl, and

[0015] R⁵ is fluorine- and/or chlorine-substituted alkyl,

[0016] by reacting1-amino-6-hydroxy-3-phenyldihydro-2,4(1H,3H)pyrimidinedione derivativesof the general formula (II)

[0017] in which

[0018] R¹, R², R³, R⁴ and R⁵ are each as defined above

[0019] are reacted with a dehydrating agent, optionally in the presenceof one or more reaction assistants and optionally in the presence of oneor more diluents, at temperatures between −30° C. and +180° C.

[0020] Preferred definitions of the radicals and groups present informula (I) are defined hereinbelow.

[0021] R¹ is preferably hydrogen, cyano, nitro, fluorine, chlorine orbromine,

[0022] R² is preferably cyano, nitro, fluorine, chlorine, bromine oroptionally fluorine- and/or chlorine-substituted alkyl or alkoxy having1 to 4 carbon atoms,

[0023] R³ is preferably hydrogen, hydroxyl, mercapto, amino,hydroxyamino, halogen, or one of the radicals —R⁶, -Q-R⁶, —NH—R⁶,—NH—O—R⁶, —NH—SO₂—R⁶, —N(SO₂—R⁶)—CQ¹-R⁶, —CQ¹-Q²-R⁶, —CQ¹-NH—R⁶,-Q²-CQ¹-R⁶, —NH—CQ¹-R⁶, —N(SO₂—R⁶)(CQ-R⁶), -Q²-CQ¹-Q²-R⁶, —NH—CQ¹-Q²-R⁶or -Q²-CQ¹-NH—R⁶,

[0024] Q is preferably O, S or SO₂,

[0025] Q¹ and Q² are preferably each oxygen.

[0026] R⁴ is preferably hydrogen, fluorine, chlorine, bromine oroptionally fluorine- and/or chlorine-substituted alkyl having 1 to 6carbon atoms.

[0027] R⁵ is preferably fluorine- and/or chlorine-substituted alkylhaving 1 to 6 carbon atoms.

[0028] R⁶ is preferably optionally cyano-, halogen-, C₁-C₄-alkoxy-,C₁-C₄-alkylthio-, C₁-C₄-alkylcarbonyl-, C₁-C₄-alkoxycarbonyl- orC₁-C₄-alkylaminocarbonyl-substituted alkyl having 1 to 6 carbon atoms,

[0029] or optionally cyano-, carboxy-, halogen-, C₁-C₄-alkylcarbonyl-,C₁-C₄-alkoxycarbonyl- or C₁-C₄-alkylaminocarbonyl-substituted alkenyl oralkinyl each having 2 to 6 carbon atoms,

[0030] or optionally cyano, carboxy, halogen, C₁-C₄-alkylcarbonyl- orC₁-C₄-alkoxycarbonyl-substituted cycloalkyl or cycloalkylalkyl eachhaving 3 to 6 carbon atoms in the cycloalkyl group and optionally 1 to 4carbon atoms in the alkyl moiety,

[0031] or optionally mono- to tri-hydroxy-, -mercapto-, -amino-,-cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-, —C₁-C₄-alkyl-,—C₁-C₄-haloalkyl-, —C₁-C₄-alkoxy-, —C₁-C₄-haloalkoxy-,—C₁-C₄-alkylthio-, —C₁-C₄-haloalkylthio-, —C₁-C₄-alkylsulphinyl-,—C₁-C₄-alkylsulphonyl-, —C₁-C₄-alkylamino- and/or-dimethylamino-substituted aryl or arylalkyl each having 6 or 10 carbonatoms in the aryl group and optionally 1 to 4 carbon atoms in the alkylmoiety,

[0032] or optionally mono- to tri-hydroxy-, -mercapto-, -amino-,-cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-, —C₁-C₄-alkyl-,—C₁-C₄-haloalkyl-, —C₁-C₄-alkoxy-, —C₁-C₄-haloalkoxy-,—C₁-C₄-alkylthio-, —C₁-C₄-haloalkylthio-, —C₁-C₄-alkylsulphinyl-,—C₁-C₄-alkylsulphonyl-, —C₁-C₄-alkylamino- and/or-dimethylamino-substituted heterocyclyl or heterocyclylalkyl having 2 to6 carbon atoms and 1 to 3 nitrogen atoms and/or 1 or 2 oxygen atomsand/or one sulphur atom in the heterocyclyl group and optionally 1 to 4carbon atoms in the alkyl moiety.

[0033] R¹ is more preferably hydrogen, fluorine or chlorine.

[0034] R² is more preferably cyano, fluorine, chlorine, bromine, methylor trifluoromethyl.

[0035] R³ is more preferably hydroxyl, mercapto, amino, fluorine,chlorine, bromine or one of the radicals —R⁶, -Q-R⁶, —NH—R⁶, —NH—O—R⁶,—NH—SO 2-R⁶, —N(SO₂—R⁶)₂—CQ¹-R⁶, —CQ¹-Q²-R⁶, —CQ₁-NH—R⁶, -Q²-CQ¹-R⁶,—NH—CQ¹-R⁶, —N(SO₂—R⁶)(CQ¹-R⁶), -Q²-CQ¹-Q²-R⁶, —NH—CQ¹-Q²-R⁶ or-Q²-CQ¹-NH—R⁶.

[0036] Q is more preferably O or SO₂.

[0037] R⁴ is more preferably hydrogen, fluorine, chlorine, bromine,methyl, ethyl or trifluoromethyl.

[0038] R⁵ is more preferably trifluoromethyl, chlorodifluoromethyl,fluorodichloromethyl or pentafluoroethyl.

[0039] R⁶ is more preferably optionally cyano-, fluorine-, chlorine-,methoxy-, ethoxy-, methylthio-, ethylthio-, acetyl-, propionyl-,methoxycarbonyl-, ethoxycarbonyl-, methylaminocarbonyl- orethylaminocarbonyl-substituted methyl, ethyl, n- or i-propyl, n-, i- ors-butyl,

[0040] or optionally cyano-, carboxy-, fluorine-, chlorine-, bromine-,acetyl-, propionyl-, n- or i-butyroyl-, methoxycarbonyl-,ethoxycarbonyl-, n- or i-propoxycarbonyl-, methylaminocarbonyl-,ethylaminocarbonyl-, n- or i-propylaminocarbonyl-substituted propenyl,butenyl, propinyl or butinyl,

[0041] or optionally cyano-, carboxy-, fluorine-, chlorine-, bromine-,acetyl-, propionyl-, methoxycarbonyl- or ethoxycarbonyl-substitutedcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl,

[0042] or optionally mono- to tri-hydroxy-, -mercapto-, -amino-,-cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-, -methyl-, -ethyl-,-trifluoromethyl-, -methoxy-, -ethoxy-, -difluoromethoxy-,-trifluoromethoxy-, -methylthio-, -ethylthio-, -difluoromethylthio-,-trifluoromethylthio-, -methylsulphinyl-, -ethylsulphinyl-,-methylsulphonyl-, -methylamino-, -ethylamino- and/or-dimethylamino-substituted phenyl, benzyl or phenylethyl,

[0043] or optionally mono- or di-hydroxy-, -mercapto-, -amino-, -cyano-,-carboxy-, -carbamoyl-, -thiocarbamoyl-, -methyl-, -ethyl-, -n- or-1-propyl-, -n-, -1-, -s- or -t-butyl-, -difluoromethyl-,-dichloromethyl-, -trifluoromethyl-, -trichloromethyl-,-chlorodifluoromethyl-, -fluorodichloromethyl-, -methoxy-, -ethoxy-,-difluoromethoxy-, -trifluoromethoxy-, -methylthio-, -ethylthio-,-difluoromethylthio-, -trifluoromethylthio-, -methylsulphinyl-,-ethylsulphinyl-, -methylsulphonyl-, -ethylsulphonyl-, -methylamino-,-ethylamino- and/or -dimethylamino-substituted heterocyclyl orheterocyclylalkyl from the group of oxiranyl, oxetanyl, furyl,tetrahydrofuryl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl,triazinyl, pyrazolylmethyl, furylmethyl, thienylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, pyridinylmethyl, pyrimidinylmethyl,

[0044] Surprisingly, the 1-amino-3-phenyluracil derivatives(1-amino-3-phenyl-2,4(1H,3H)pyrimidinedione derivatives) of the generalformula (I) can be prepared by the process according to the invention inconsiderably better yields and in higher purity than by the processesknown hitherto.

[0045] The process according to the invention is notable for a series ofadvantages. For instance, the starting materials required are obtainablein a simple manner and also in relatively large amounts. In addition,carrying out the reaction according to the invention and the isolationof the desired substances presents no problems worthy of mention.

[0046] When the starting material used is1-amino-3-(4-cyano-2,5-difluorophenyl)dihydro-6-hydroxy-6-trifluoromethyl-2,4(1H,3H)pyrimidinedioneand the dehydrating agent used is oxalyl chloride, the course of theprocess according to the invention can be outlined by the followingscheme:

[0047] The 1-amino-6-hydroxy-3-phenyldihydro-1,4(1H,3H)-pyrimidinedionederivatives required as starting materials when carrying out the processaccording to the invention are generally defined by formula (II).Preference is given to using compounds of the formula (II) in which

[0048] R¹ is hydrogen, cyano, nitro, fluorine, chlorine or bromine,

[0049] R² is cyano, nitro, fluorine, chlorine, bromine or optionallyfluorine- and/or chlorine-substituted alkyl or alkoxy having 1 to 4carbon atoms,

[0050] R³ is hydrogen, hydroxyl, mercapto, amino, hydroxyamino, halogen,or one of the radicals —R⁶, -Q-R⁶, —NH—R⁶, —NH—O—R⁶, —NH—SO₂—R⁶,—N(SO₂—R⁶)₂, —CQ¹-R⁶, —CQ¹-Q²-R⁶, —CQ¹-NH—R⁶, -Q²-CQ -R⁶, —NH—CQ¹-R⁶,—N(SO₂R⁶)(CQ¹-R⁶), Q²-CQ¹-Q²-R⁶, —NH—CQ¹-Q²-R⁶ or -Q²-CQ -NH—R,

[0051] where

[0052] Q is O, S, SO or SO₂,

[0053] Q¹ and Q² are each independently oxygen or sulphur and

[0054] R⁶ is optionally cyano-, halogen-, C₁-C₄-alkoxy-,C₁-C₄-alkylthio-, C₁-C₄-alkylcarbonyl-, C₁-C₄-alkoxycarbonyl- orC₁-C₄-alkylaminocarbonyl-substituted alkyl having 1 to 6 carbon atoms,

[0055] or optionally cyano-, carboxy-, halogen-, C₁-C₄-alkylcarbonyl-,C₁-C₄-alkoxycarbonyl- or C₁-C₄-alkylaminocarbonyl-substituted alkenyl oralkinyl each having 2 to 6 carbon atoms,

[0056] or optionally cyano, carboxy, halogen, C₁-C₄-alkylcarbonyl- orC₁-C₄-alkoxycarbonyl-substituted cycloalkyl or cycloalkylalkyl eachhaving 3 to 6 carbon atoms in the cycloalkyl group and optionally 1 to 4carbon atoms in the alkyl moiety,

[0057] or optionally mono- to tri-hydroxy-, -mercapto-, -amino-,-cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-, —C₁-C₄-alkyl-,—C₁-C₄-haloalkyl-, —C₁-C₄-alkoxy-, —C₁-C₄-haloalkoxy-,—C₁-C₄-alkylthio-, —C₁-C₄-haloalkylthio-, —C₁-C4-alkylsulphinyl-,—C₁-C₄-alkylsulphonyl-, —C₁-C₄-alkylamino- and/or-dimethylamino-substituted aryl or arylalkyl each having 6 or 10 carbonatoms in the aryl group and optionally 1 to 4 carbon atoms in the alkylmoiety,

[0058] or optionally mono- to tri-hydroxy-, -mercapto-, -amino-,-cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-, —C₁-C₄-alkyl-,—C₁-C₄-haloalkyl-, —C₁-C₄-alkoxy-, —C₁-C₄-haloalkoxy-,—C₁-C₄-alkylthio-, —C₁-C₄-haloalkylthio-, —C₁-C₄-alkylsulphinyl-,—C₁-C4-alkylsulphonyl-, —C₁-C₄-alkylamino- and/or-dimethylamino-substituted heterocyclyl or heterocyclylalkyl having 2 to6 carbon atoms and 1 to 3 nitrogen atoms and/or 1 or 2 oxygen atomsand/or one sulphur atom in the heterocyclyl group and optionally 1 to 4carbon atoms in the alkyl moiety,

[0059] R⁴ is hydrogen, fluorine, chlorine, bromine or optionallyfluorine- and/or chlorine-substituted alkyl having 1 to 6 carbon atomsand

[0060] R⁵ is fluorine- and/or chlorine-substituted alkyl having 1 to 6carbon atoms.

[0061] Particularly preferred definitions of the radicals and groupspresent in (II) are defined hereinbelow.

[0062] R¹ is preferably hydrogen, fluorine or chlorine.

[0063] R² is preferably cyano, fluorine, chlorine, bromine, methyl ortrifluoromethyl.

[0064] R³ is preferably hydroxyl, mercapto, amino, fluorine, chlorine,bromine or one of the radicals —R⁶, -Q-R⁶, —NH—R⁶, —NH—O—R⁶, —NH—SO₂—R⁶,—N(SO₂—R⁶)₂, —CQ¹-R⁶-CQ¹-Q²-R⁶, —CQ¹-NH—R⁶, -Q²-CQ¹-R⁶, —NH—CQ¹-R⁶,—N(SO₂—R⁶)(CQ¹R⁶) Q²-CQ¹-Q²-R⁶, —NH—CQ¹-Q²-R⁶ or -Q²-CQ¹-NH—R⁶.

[0065] Q is preferably O, S or SO₂.

[0066] Q¹ and Q² are each independently preferably oxygen.

[0067] R⁴ is preferably hydrogen, fluorine, chlorine, bromine, methyl,ethyl or trifluoromethyl.

[0068] R⁵ is preferably trifluoromethyl, chlorodifluoromethyl,fluorodichloromethyl or pentafluoroethyl.

[0069] R⁶ is preferably optionally cyano-, fluorine-, chlorine-,methoxy-, ethoxy-, methylthio-, ethylthio-, acetyl-, propionyl-,methoxycarbonyl-, ethoxycarbonyl-, methylaminocarbonyl- orethylaminocarbonyl-substituted methyl, ethyl, n- or i-propyl, n-, i- ors-butyl,

[0070] or optionally cyano-, carboxy-, fluorine-, chlorine-, bromine-,acetyl-, propionyl-, n- or i-butyroyl-, methoxycarbonyl-,ethoxycarbonyl-, n- or i-propoxycarbonyl-, methylaminocarbonyl-,ethylaminocarbonyl-, n- or i-propylaminocarbonyl-substituted propenyl,butenyl, propinyl or butinyl,

[0071] or optionally cyano-, carboxy-, fluorine-, chlorine-, bromine-,acetyl-, propionyl-, methoxycarbonyl- or ethoxycarbonyl-substitutedcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl,

[0072] or optionally mono- to tri-hydroxy-, -mercapto-, -amino-,-cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-, -methyl-, -ethyl-,-trifluoromethyl-, -methoxy-, -ethoxy-, -difluoromethoxy-,-trifluoromethoxy-, -methylthio-, -ethylthio-, -difluoromethylthio-,-trifluoromethylthio-, -methylsulphinyl-, -ethylsulphinyl-,-methylsulphonyl-, -methyl-amino-, -ethylamino- and/or-dimethylamino-substituted phenyl, benzyl or phenylethyl,

[0073] or optionally mono- or di-hydroxy-, -mercapto-, -amino-, -cyano-,-carboxy-, -carbamoyl-, -thiocarbamoyl-, -methyl-, -ethyl-, -n- or-1-propyl-, -n-, -1-, -s- or -t-butyl-, -difluoromethyl-,-dichloromethyl-, -trifluoromethyl-, -trichloromethyl-,-chlorodifluoromethyl-, -fluorodichloromethyl-, -methoxy-, -ethoxy-,-difluoromethoxy-, -trifluoromethoxy-, -methylthio-, -ethylthio-,-difluoromethylthio-, -trifluoromethylthio-, -methylsulphinyl-,-ethylsulphinyl-, -methylsulphonyl-, -ethylsulphonyl-, -methylamino-,-ethylamino- and/or -dimethylamino-substituted heterocyclyl orheterocyclylalkyl from the group of oxiranyl, oxetanyl, furyl,tetrahydrofuryl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl,triazinyl, pyrazolylmethyl, furylmethyl, thienylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, pyridinylmethyl, pyrimidinylmethyl.

[0074] R¹ is more preferably hydrogen, fluorine or chlorine.

[0075] R² is more preferably cyano.

[0076] R³ is more preferably one of the radicals —NH—R⁶, —NH—O—R⁶,NH—SO₂—R⁶—, —NH—CQ¹-R⁶ or —N(SO₂—R⁶)(CQ¹-R⁶).

[0077] Q is more preferably O or SO₂.

[0078] R⁶ is more preferably optionally fluorine- and/orchlorine-substituted methyl, ethyl or n- or i-propyl,

[0079] or optionally cyano-, fluorine- and/or chlorine-substitutedpropenyl or butenyl,

[0080] or optionally cyano-, fluorine-, chlorine- or acetyl-substitutedcyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclopentylmethyl or cyclohexylmethyl,

[0081] or optionally mono- to tri-hydroxy-, -carboxy-, -methyl-,-ethyl-, -trifluoromethyl-, -methoxy- or -ethoxy-substituted phenyl,benzyl or phenylethyl,

[0082] or optionally mono- or di-hydroxy-, -amino-, -methyl-, -ethyl-,-trifluoromethyl-, -methoxy- or -ethoxy-substituted heterocyclyl orheterocyclylalkyl from the group of furyl, tetrahydrofuryl, thienyl,tetrahydrothienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, thiadiazolyl, pyrazolylmethyl, furylmethyl, thienylmethyl orthiazolylmethyl.

[0083] The starting materials of the general formula (II) are not yetdisclosed by the literature; as novel substances, they also form part ofthe subject-matter of the present application.

[0084] The novel1-amino-6-hydroxy-3-phenyldihydro-1,4(1H,3H)pyrimidinedione derivativesof the general formula (II) are obtained when3-phenyl-2H-1,3-oxazine-2,4-(3H)dione derivatives of the general formula(III)

[0085] in which

[0086] R¹, R², R³, R⁴ and R⁵ are each as defined above,

[0087] are reacted with hydrazine, hydrazine hydrate or an acid adductof hydrazine, for example hydrazine acetate, hydrazine hydrochloride orhydrazine sulphate, preferably with hydrazine hydrate,

[0088] optionally in the presence of a reaction assistant and/ordiluent, for example acetic acid or propionic acid, at temperaturesbetween −30° C. and +100° C., preferably between −10° C. and +80° C.

[0089] The 3-phenyl-2H-1,3-oxazine-2,4(3H)dione derivatives of thegeneral formula (III) are known and/or can be prepared by processesknown per se (cf. EP-A-371240, EP-A-638563, WO-A-98/27057,WO-A-98/27067, WO-A-98/27068).

[0090] The process according to the invention for preparing1-amino-3-phenyluracil derivatives(1-amino-3-phenyl-2,4(1H,3H)pyrimidinedione derivatives) of the generalformula (I) is carried out with the use of a dehydrating agent. Usefuldehydrating agents in this context are the customary water-removingsubstances. Preferred groups of dehydrating agents are: carbodiimides,e.g. dicyclohexylcarbodiimide, orthoesters, e.g. trimethyl or triethylorthoformate, acids, e.g. hydrochloric acid, sulphuric acid,methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid ortrifluoroacetic acid, acid anhydrides, e.g. acetic anhydride, propionicanhydride, phosphorus(V) oxide or sulphur trioxide, acid chlorides, e.g.phosgen, oxalyl chloride, thionyl chloride, sulphuryl chloride,phosphoryl chloride, phosphorus(V) chloride, diethyl chlorophosphate,acetyl chloride, chlorotrimethylsilane, methanesulphonyl chloride,benzenesulphonyl chloride, p-toluenesulphonyl chloride, or Lewis acids,e.g. boron trifluoride or aluminium trichloride.

[0091] Very particular preference is given to using thionyl chloride asthe dehydrating agent in the process according to the invention.

[0092] The process according to the invention for preparing1-amino-3-phenyluracil derivatives(1-amino-3-phenyl-2,4(1H,3H)pyrimidinedione derivatives) of the generalformula (I) is carried out using one or more reaction assistants. Usefulreaction assistants when carrying out the process according to theinvention are all customary inorganic or organic bases. Preference isgiven to using alkali metal or alkaline earth metal, acetates, amides,carbonates, hydrogen carbonates, hydrides, hydroxides or alkoxides, forexample sodium acetate, potassium acetate or calcium acetate, lithiumamide, sodium amide, potassium amide or calcium amide, sodium carbonate,potassium carbonate or calcium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate or calcium hydrogencarbonate, lithiumhydride, sodium hydride, potassium hydride or calcium hydride, lithiumhydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide,sodium or potassium methoxide, ethoxide, n- or i-propoxide, n-, i-, s-or t-butoxide; and also basic organic nitrogen compounds, for exampletrimethylamine, triethylamine, tripropylamine, tributylamine,ethyl-diisopropylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine,ethyldicyclohexylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine,pyridine, 2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-,3,4-dimethyl- and 3,5-dimethylpyridine, 5-ethyl-2-methylpyridine,4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine,N-methylmorpholine, N-ethylmorpholine, 1,4-diazabicyclo[2,2,2]octane(DABCO), 1,5-diazabicyclo[4,3,0]non-5-ene (DBN), or1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

[0093] The abovementioned basic organic nitrogen compounds, inparticular pyridine, are used with very particular preference asreaction assistants in the process according to the invention.

[0094] The process according to the invention for preparing1-amino-3-phenyluracil derivatives(1-amino-3-phenyl-2,4(1H,3H)pyrimidinedione derivatives) of the generalformula (1) is carried out using one or more diluents. Useful diluentswhen carrying out the process according to the invention are allcustomary inert, organic solvents.

[0095] Preference is given to using aliphatic, alicyclic or aromatic,optionally halogenated hydrocarbons, for example benzine, benzene,toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether,hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride;ethers such as diethyl ether, diisopropyl ether, dioxane,tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; ketonessuch as acetone, butanone or methyl isobutyl ketone; nitriles such asacetonitrile, propionitrile or n- or i-butyronitrile; amides such asN,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylformamide,N,N-dibutylformamide, N,N-dimethylacetamide, N-methylformanilide,N-methylpyrrolidone or hexamethylphosphoramide; esters such as methylacetate or ethyl acetate, sulphoxides such as dimethyl sulphoxide.

[0096] Very particular preference is given to using aprotic polarsolvents, for example methyl isobutyl ketone, acetonitrile,propionitrile or n- or i-butyronitrile, N,N-dimethylformamide orN,N-dimethylacetamide, as diluents in the process according to theinvention.

[0097] When carrying out the process according to the invention forpreparing compounds of the formula (1), the reaction temperatures can bevaried within a relatively wide range. The working temperatures aregenerally between −30° C. and +180° C., preferably between −10° C. and+150° C., more preferably between 0° C. and 100° C.

[0098] The process according to the invention is generally carried outworking under atmospheric pressure. However, it is also possible to workunder elevated pressure or, as long as no volatile components are used,under reduced pressure.

[0099] To carry out the process according to the invention, generallybetween 0.2 and 2 mol, preferably between 0.5 and 1.5 mol, of adehydrating agent are used per mole of1-amino-6-hydroxy-3-phenyldihydro-2,4(1H,3H)pyrimidinedione derivativeof the formula (II).

[0100] In a preferred embodiment of the process according to theinvention, the amino-6-hydroxy-3-phenyldihydro-2,4(1H,3H)pyrimidinedionederivative of the formula (II) is initially charged in a suitablediluent, and the dehydrating agent and also reaction assistants aremetered in slowly. The reaction mixture is then stirred, optionally atelevated temperature, up to the end of the reaction. The workup iseffected by customary methods (cf. the preparation examples).

[0101] The 1-amino-3-phenyluracil derivatives of the formula (I) can beused as herbicides for controlling weeds (cf. EP-A-648 749,WO-A-94/04511, WO-A-95/29168, WO-A-96/35679).

PREPARATION EXAMPLES Example 1

[0102]

[0103] 25.5 g (97.5%, 56.7 mMol) ofN-[5-(3-amino-4-hydroxy-2,6-dioxo-4-trifluoromethyl-tetrahydro-1(2B)-pyrimidinyl)-2-cyano-4-fluorophenyl]ethanesulphonamide areinitially charged in 100 ml of n-butyronitrile and 224 mg (2.8 mMol) ofpyridine are added at room temperature (approx. 20° C.). 33.7 g ofthionyl chloride are added dropwise to the suspension. Slight gasevolution takes place and the reaction mixture becomes yellow. Afterabout a minute, a clear solution has formed, cloudiness sets in afterabout 5 minutes and a voluminous precipitate has formed after about 10minutes. The mixture is heated to reflux temperature and stirred for afurther 30 minutes, and significant gas evolution sets in above about60° C. After cooling to room temperature, the mixture is diluted with 50ml of n-butyronitrile, 100 ml of ice-water are added, the phases areseparated, and the organic phase is washed three times with a littlewater, dried over sodium sulphate and filtered. The solvent is carefullydistilled off from the filtrate under reduced pressure.

[0104] 22.6 g (94% according to 19F NMR quantification, 89% of theory)of N-[5-(3-amino-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-1(2H)-pyrimidinyl)-2-cyano-4-fluorophenyl]ethanesulphonamide of meltingpoint 190° C. are obtained.

[0105] Starting Materials of the Formula (II):

Example (II-1)

[0106]

[0107] 60.7 g (99.3%, 150 mmol) ofN-[2-cyano-5-(2,4-dioxo-6-trifluoromethyl-2H-1,3-oxazin-3(4H)-yl)-4-fluorophenyl]ethanesulphonamideare initially charged in 300 ml of propionic acid, and 9.0 g ofhydrazine hydrate (99%, 178 mmol) are added with stirring at roomtemperature (approx. 20° C.). The mixture (suspension) heats to approx.30° C. and the suspension is stirred at this temperature for 5 hours,while the colour lightens. The mixture is then cooled to 15° C. andfiltered with suction, and the filter residue is triturated with aspatula on the suction filter and washed repeatedly with isopropanol andsucked to dryness. The slightly yellowish filtercake is initially driedunder air and then overnight in a desiccator over potassium hydroxide.

[0108] 41 g (94.9%, 60% of theory) ofN-[5-(3-amino-4-hydroxy-2,6-dioxo-4-trifluoromethyltetrahydro-1(2H)-pyrimidinyl)-2-cyano-4-fluorophenyl]ethanesulphonamide having amelting point of 182° C. (decomposition) are obtained.

[0109] After concentrating the mother liquor, the residue, according toHPLC analysis, still contains 35.5% ofN-[5-(3-amino-4-hydroxy-2,6-dioxo-4-trifluoromethyltetrahydro-1(2H)-pyrimidinyl)-2-cyano-4-fluorophenyl]ethanesulphonamide(corresponds to a further 23% of the theoretical yield). This thereforeresults in a total yield of 83% of theory.

1. Process for preparing compounds of the formula (1)

in which R¹ is hydrogen, cyano, nitro or halogen, R² is cyano, nitro,halogen or optionally substituted alkyl or alkoxy, R³ is hydrogen,hydroxyl, mercapto, amino, hydroxyamino, hydrazino, halogen, or one ofthe radicals —R⁶, -Q-R⁶, —NH—R⁶, —NH—O—R⁶, —NH—SO₂—R⁶, —N(SO₂—R⁶)₂,—CQ¹-R⁶, —CQ¹-Q²-R⁶¹—CQ¹-NH—R⁶, Q²-CQ¹-R⁶, —NH—CQ¹-R⁶,—N(SO₂—R⁶)(CQ¹-R⁶), -Q²-CQ¹-Q²-R⁶, NH-CQ¹-Q²-R⁶ or -Q²-CQ¹-NH—R⁶, whereQ is O, S, SO or SO₂, Q¹ and Q² are each independently oxygen or sulphurand R⁶ is optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, R⁴is hydrogen, halogen or optionally substituted alkyl, and R⁵ isfluorine- and/or chlorine-substituted alkyl, characterized in thatcompounds of the formula (II)

in which R¹, R², R³, R⁴ and R⁵ are each as defined above are reactedwith a dehydrating agent at temperatures between −30° C. and +180° C. 2.Process according to claim 1, characterized in that compounds of theformula (II) are reacted in which R¹ is hydrogen, cyano, nitro,fluorine, chlorine or bromine, R² is cyano, nitro, fluorine, chlorine,bromine or optionally fluorine- and/or chlorine-substituted alkyl oralkoxy having 1 to 4 carbon atoms, R³ is hydrogen, hydroxyl, mercapto,amino, hydroxyamino, halogen, or one of the radicals —R⁶, -Q-R⁶, —NH—R⁶,—NH—O—R⁶, —NH—SO₂—R⁶, —N(SO₂—R⁶)₂, —CQ¹-R⁶, —CQ¹-Q²-R⁶, —CQ¹-NH—R⁶,-Q²-CQ¹-R⁶, —NH—CQ¹-R⁶, —N(SO₂—R⁶)(CQ¹-R⁶), -Q²-CQ¹-Q²-R⁶, —NH—CQ¹-Q²-R⁶or -Q²-CQ¹-NH—R⁶, where Q is O, S, SO or SO₂, Q¹ and Q² are eachindependently oxygen or sulphur and R⁶ is optionally cyano-, halogen-,C₁-C₄-alkoxy-, C₁-C₄-alkylthio-, C₁-C₄-alkylcarbonyl-,C₁-C₄-alkoxycarbonyl- or C₁-C₄-alkylaminocarbonyl-substituted alkylhaving 1 to 6 carbon atoms, or optionally cyano-, carboxy-, halogen-,C₁-C₄-alkylcarbonyl-, C₁-C₄-alkoxycarbonyl- orC₁-C₄-alkylaminocarbonyl-substituted alkenyl or alkinyl each having 2 to6 carbon atoms, or optionally cyano, carboxy, halogen,C₁-C₄-alkylcarbonyl- or C₁-C₄-alkoxycarbonyl-substituted cycloalkyl orcycloalkylalkyl each having 3 to 6 carbon atoms in the cycloalkyl groupand optionally 1 to 4 carbon atoms in the alkyl moiety, or optionallymono- to tri-hydroxy-, -mercapto-, -amino-, -cyano-, -carboxy-,-carbamoyl-, -thiocarbamoyl-, —C₁-C₄-alkyl-, —C₁-C₄-haloalkyl-,—C₁-C₄-alkoxy-, —C₁-C₄-haloalkoxy-, —C₁-C₄-alkylthio-,—C₁-C₄-haloalkylthio-, —C₁-C₄-alkylsulphinyl-, —C₁-C₄-alkylsulphonyl-,—C₁-C₄-alkylamino- and/or -dimethylamino-substituted aryl or arylalkyleach having 6 or 10 carbon atoms in the aryl group and optionally 1 to 4carbon atoms in the alkyl moiety, or optionally mono- to tri-hydroxy-,-mercapto-, -amino-, -cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-,—C₁-C₄-alkyl-, —C₁-C₄-haloalkyl-, —C₁-C₄-alkoxy-, —C₁-C₄-haloalkoxy-,—C₁-C₄-alkylthio-, —C₁-C₄-haloalkylthio-, —C₁-C₄-alkylsulphinyl-,—C₁-C₄-alkylsulphonyl-, —C₁-C₄-alkylamino- and/or-dimethylamino-substituted heterocyclyl or heterocyclylalkyl having 2 to6 carbon atoms and 1 to 3 nitrogen atoms and/or 1 or 2 oxygen atomsand/or one sulphur atom in the heterocyclyl group and optionally 1 to 4carbon atoms in the alkyl moiety, R⁴ is hydrogen, fluorine, chlorine,bromine or optionally fluorine- and/or chlorine-substituted alkyl having1 to 6 carbon atoms and R⁵ is fluorine- and/or chlorine-substitutedalkyl having 1 to 6 carbon atoms.
 3. Process according to claim 1,characterized in that compounds of the formula (II) are reacted in whichR¹ is hydrogen, fluorine or chlorine, R² is cyano, fluorine, chlorine,bromine, methyl or trifluoromethyl, R³ is hydroxyl, mercapto, amino,fluorine, chlorine, bromine or one of the radicals —R⁶, -Q-R⁶, —NH—R⁶,—NH—O—R⁶, —NH—SO₂—R⁶, —N(SO₂—R⁶)₂, CQ¹-R⁶, —CQ¹-Q²-R⁶, —CQ¹-NH—R⁶,-Q²-CQ¹-R⁶, —NH—CQ¹-R⁶, —N(SO₂—R⁶)(CQ¹-R⁶), -Q²-CQ¹-Q²-R⁶, —NH—CQ¹-Q²-R⁶or -Q²-CQ¹—NH—R⁶, where Q is O, S, SO or SO₂, Q¹ and Q² are eachindependently oxygen or sulphur and R⁶ is optionally cyano-, fluorine-,chlorine-, methoxy-, ethoxy-, methylthio-, ethylthio-, acetyl-,propionyl-, methoxycarbonyl-, ethoxycarbonyl-, methylaminocarbonyl- orethylaminocarbonyl-substituted methyl, ethyl, n- or i-propyl, n-, i- ors-butyl, or optionally cyano-, carboxy-, fluorine-, chlorine-, bromine-,acetyl-, propionyl-, n- or i-butyroyl-, methoxycarbonyl-,ethoxycarbonyl-, n- or i-propoxycarbonyl-, methylaminocarbonyl-,ethylaminocarbonyl-, n- or i-propylaminocarbonyl-substituted propenyl,butenyl, propinyl or butinyl, or optionally cyano-, carboxy-, fluorine-,chlorine-, bromine-, acetyl-, propionyl-, methoxycarbonyl- orethoxycarbonyl-substituted cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl orcyclohexylmethyl, or optionally mono- to tri-hydroxy-, -mercapto-,-amino-, -cyano-, -carboxy-, -carbamoyl-, -thiocarbamoyl-, -methyl-,-ethyl-, -trifluoromethyl-, -methoxy-, -ethoxy-, -difluoromethoxy-,-trifluoromethoxy-, -methylthio-, -ethylthio-, -difluoromethylthio-,-trifluoromethylthio-, -methylsulphinyl-, -ethylsulphinyl-,-methylsulphonyl-, -methylamino-, -ethylamino- and/or-dimethylamino-substituted phenyl, benzyl or phenylethyl, or optionallymono- or di-hydroxy-, -mercapto-, -amino-, -cyano-, -carboxy-,-carbamoyl-, -thiocarbamoyl-, -methyl-, -ethyl-, -n- or -1-propyl-, -n-,-1-, -s- or -t-butyl-, -difluoromethyl-, -dichloromethyl-,-trifluoromethyl-, -trichloromethyl-, -chlorodifluoromethyl-,-fluorodichloromethyl-, -methoxy-, -ethoxy-, -difluoromethoxy-,-trifluoromethoxy-, -methylthio-, -ethylthio-, -difluoromethylthio-,-trifluoromethylthio-, -methylsulphinyl-, -ethylsulphinyl-,-methylsulphonyl-, -ethylsulphonyl-, -methylamino-, -ethylamino- and/or-dimethylamino-substituted heterocyclyl or heterocyclylalkyl from thegroup of oxiranyl, oxetanyl, furyl, tetrahydrofuryl, dioxolanyl,thienyl, tetrahydrothienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyridinyl, pyrimidinyl, triazinyl, pyrazolylmethyl,furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl,thiazolylmethyl, pyridinylmethyl, pyrimidinylmethyl, R⁴ is hydrogen,fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl and R⁵ istrifluoromethyl, chlorodifluoromethyl, fluorodichloromethyl orpentafluoroethyl.
 4. Compounds of the formula (II)

in which R¹, R², R³, R⁴ and R⁵ are each as defined in any of claims 1 to3.
 5. Process for preparing compounds of the formula (II) according toclaim 4, characterized in that compounds of the formula (III)

in which R¹, R², R³, R⁴ and R⁵ are each as defined in any of claims 1 to3 are reacted with hydrazine, hydrazine hydrate or an acid adduct ofhydrazine at temperatures between −30° C. and +100° C.
 6. Processaccording to claim 1, characterized in that the reaction is carried outin the presence of one or more reaction assistants.
 7. Process accordingto claim 1 or 6, characterized in that the reaction is carried out inthe presence of one or more diluents.
 8. Process according to one ofclaims 1, 6 or 7, characterized in that the dehydrating agent used is acarbodiimide, orthoester, acid, acid anhydride, acid chloride or Lewisacid.
 9. Process according to one of claims 1 or 6 to 8, characterizedin that the dehydrating agent used is thionyl chloride.
 10. Processaccording to one of claims 6 to 9, characterized in that the reactionassistant used is a basic organic nitrogen compound.
 11. Processaccording to claim 10, characterized in that the reaction assistant usedis pyridine.
 12. Process according to claim 7, characterized in that thediluent used is an aprotic polar solvent.
 13. Process according to claim1, characterized in that the reaction is carried out at temperaturesbetween −10° C. and +150° C.